Tiacumicin compounds are naturally occurring compounds with an antibiotic activity that can be obtained by cultivating various microorganisms belonging to the Actinoplanes family (especially the genus Dactylosporangium aurantiacum, subspecies hamdenensis) in a suitable nutrient medium at a suitable temperature and isolating the compounds having antibiotic activity against a variety of microorganisms (tiacumicins A-F; U.S. Pat. No. 4,918,174). Especially tiacumicins B and C turned out to possess antibiotic activity against a number of Gram-positive bacteria in vitro including strains resistant to therapeutic antibiotics, used at the time. U.S. Pat. No. 5,583,115 discloses dialkyltiacumicin compounds, which are derivatives of the above-mentioned tiacumicin compounds A-F, were found to have in vitro activity against a variety of bacterial pathogens and in particular against Clostridium species. U.S. Pat. No. 5,767,096 discloses bromotiacumicin compounds, which are also derivatives of tiacumicin compounds A-F, which were found to have in vitro activity against some bacterial pathogens and in particular against Clostridium species.
From a chemical point of view the tiacumicins share an 18-membered macrocyclic ring, which is glycosidically attached to one or two optionally substituted sugar molecules (U.S. Pat. No. 4,918,174 and WO 2004/014295) as follows:

WO 2004/014295 describes substantially pure R-tiacumicins, obtained by submerged aerobic fermentation of Dactylosporangium aurantiacum hamdenensis. WO 2006/085838 discloses pharmaceutical compositions containing R-tiacumicins and especially R-tiacumicin B, which contains an R-hydroxy-group at C19, which shows surprisingly lower MIC values when tested in vitro against Clostridium species than the optically pure S-isomer of tiacumicin B and other tiacumicin related compounds.
Chinese patent applications having publication numbers 102030791 and 102219815 respectively and S. Niu et al. (2011) in ChemBioChem 12: page 1740-1748 describe 11 new tiacumicin analogues all lacking the 2′-O-methyl group on the internal rhamnose moiety. Two of those analogues have shown to have improved antibacterial properties.
R-tiacumicin B is also known under the name fidaxomicin (3-[[[6-deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-O-methyl-β-D-mannopyranosyl]oxy]methyl]-12(R)-[[6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-D-lyxo-hexopyranosyl]oxy]-11(S)-ethyl-8(S)-hydroxy-18(S)-(1(R)-hydroxyethyl)-9,13,15-trimethyloxacyclooctadeca-3,5,9,13,15-pentaene-2-one or oxacyclooctadeca-3,5,9,13,15-pentaen-2-one, 3-[[[6-deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-O-methyl-β-D-mannopyranosyl]oxy]methyl]-12-[[6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-D-lyxo-hexopyranosyl]oxy]-11-ethyl-8-hydroxy-18-[(1R)-1-hydroxyethyl]-9,13,15-trimethyl-, (3E,5E,8S,9E,11S,12R,13E,15E,18S)). It is a compound that has a narrow antimicrobial spectrum, with activity against Clostridium difficile and most strains of staphylococci and enterococci but negligible activity against gram-negative organisms and fungi. It is obtained by fermentation of Dactylosporangium aurantiacum and corresponds to the following formula (II):

According to an in vitro BCS study, fidaxomicin is a BCS (Biopharmaceutics Classification System) Class IV compound (low solubility, low permeability). Upon oral administration fidaxomicin is poorly absorbed from the intestinal tract and is therefore associated with a low incidence of systemic side effects.
Tablets containing 200 mg fidaxomicin are commercially available in Europe (under the trademark Dificlir) and in the USA (under the trademark Dificin).
Not pre-published international patent application PCT/EP2014/000091 discloses compositions containing a tiacumicin compound in admixture with an excipient, selected from the group consisting of xanthan gum, carrageenan, sodium alginate, guar gum, water dispersible cellulose (microcrystalline cellulose and sodium carboxymethylcellulose) and mixtures thereof, which is used as an anti-foaming agent for the preparation of stabilised suspension formulations.
Fidaxomicin is indicated for the treatment of Clostridium difficile infections (CDI) also known as C. difficile-associated diarrhea or disease (CDAD) and prevention of recurrences. CDI is a major burden on healthcare facilities worldwide (Wiegand P. N., Nathwani D., Wilcox M. H. et al. in J. Hosp Infect of 10 Apr. 2012; Ghantoji S. S., Sail, K. Lairson D. R. (2010) in J. Hosp. Infect. 74: 309-318). These infections are normally caused by changes in the composition and function of the intestinal flora following the use of antimicrobials and are called antibiotic-associated diarrhea (AAD).
A Clostridium difficile infection is a type of bacterial infection that can affect the digestive system. It most commonly affects people who have been treated with antibiotics. The symptoms of a C. difficile infection can range from mild to severe and include diarrhea, a high temperature (fever) of above 38° C. and painful abdominal cramps. A C. difficile infection can also lead to life-threatening complications such as severe swelling of the bowel from a build-up of gas (toxic megacolon). Clostridium difficile infections (CDI) also known as C. difficile-associated disease (CDAD) refers to a wide spectrum of diarrheal illnesses caused by the toxins produced by this organism, including cases of severe colitis with or without the presence of pseudomembranes. The occurrence of AAD varies greatly and is influenced by a number of factors, including nosocomial outbreaks, patterns of antimicrobial prescription, and individual susceptibility. It is estimated that 10% to 15% of all hospitalized patients treated with antibiotics will develop AAD. Most important, twice as many will become asymptomatic carriers. Risk factors include compromised immune status, advanced age, abdominal surgery, comorbidity, types and prolonged use of antibiotics, reduced gastric acid, and the length of hospitalization. For example, infection rates for C. difficile are reported to be around 10% after 2 weeks of hospitalization but may reach 50% after 4 or more weeks (McFarland L V. Epidemiology, risk factors and treatments for antibiotic-associated diarrhea. Dig Dis 1998; 16:292-307). All groups of antibiotics may cause AAD, but those with broad-spectrum coverage—in particular cephalosporins, fluoroquinolones, extended-coverage penicillins, and clindamycin—are the most common culprits (Wistrom J, Norrby S R, Myhre E, et al. Frequency of antibiotic-associated diarrhoea in 2462 antibiotic-treated hospitalized patients: a prospective study. J Antimicrob Chemother 2001; 47:43-50).
Treatment options are limited and are associated with effects on gut microflora recovery of the patients and high rates of recurrence.
Therefore it remains a need for improved treatment options and dosage regimens. Along with its narrow antimicrobial spectrum, fidaxomicin also has a prolonged postantibiotic effect against C. difficile. Besides the obvious benefit to the patient, the prevention of recurrence would eliminate the costs of treating additional episodes of C. difficile infection and should reduce the rate of person-to-person transmission. The currently recommended treatment regimen for adults and elderly people (65 years and older) is 200 mg administered twice daily (q12 h) for 10 days.
This is an effective treatment for CDI, and is associated with reduced rates of recurrence as compared with vancomycin. However, this treatment/dosing regimen was not optimised for recovery of microflora but chosen based on existing practice for vancomycin and metronidazole. Both vancomycin and metronidazole disrupt microflora and so on recovery cannot start until after treatment has been removed.
In two Phase III randomised, double-blind, clinical trials, fidaxomicin demonstrated non-inferiority to vancomycin for initial clinical cure of CDI, but superiority in reduction of recurrence and sustained clinical response (Crook et al. (2012) in Clin. Infect. Dis. 55(Suppl 2): S93-103).
In phase III clinical trials the risk of fidaxomicin or vancomycin treatment failure doubled for each treatment day less than 10 days (T. Louie et al. Poster presented at 22nd European Congress of Clinical Microbiology & Infectious Diseases, Mar. 31-Apr. 3, 2012, London). The relatively low impact of fidaxomicin on gut microflora may allow better recovery of bacteria during prolonged treatment periods, so reducing risk of CDI recurrence (T. J. Louie et al. (2012) in Clin. Infect. Dis. 55(S2) S132-142; Tannock in Microbiology (2010), 156, 3354-3359 (Phase II trials)).
The management of C. difficile infections (CDI), thus, is complicated by high recurrence rates with over 50% of second episodes experiencing a recurrence (RCDI). Guidelines recommend managing multiple recurrences with a vancomycin taper. No clear recommendation is available for patients failing this approach. In a recent case series report (Soriano et al in Exp Rev Antiinf Ther 2013; 11:767-776), patients with multiple RCDI that were refractory to vancomycin taper therapy were given either fidaxomicin 200 mg BID for 10 days (FID-TX), or a repeat of CDI treatment followed by either a 10-day fidaxomicin regimen as a chaser (FID-CH), or a taper as 200 mg daily for 7 days, followed by 200 mg QOD for 7-26 days (FID-TP). Demographic information, CDI history, treatment outcomes, and symptom-free interval (SFI) were collected from patient records. Treatment success was considered if symptoms resolved by the end of therapy and no additional antibiotic was needed. RCDI was defined by the onset of CDI symptoms following successful treatment for a previous episode. 14 patients received 18 courses of fidaxomicin for RCDI (mean age of 60, mean of 4.6 previous CDI episodes, mean of 2.3 previous vancomycin taper courses). All 18 courses resulted in treatment success (3 courses as FID-TX, 8 as FID-CH, and 7 as FID-TP). Of 3 FID-TX courses, there were 2 RCDI episodes (66%). When excluding RCDI due to antimicrobial exposure, there were 2 RCDI (25%) observed after the 8 FID-CH courses and no RCDI following the 7 FID-TP courses. The average SFI following a vancomycin taper was 37 days. The average SFI following FID-TX, FID-CH, and FID-TP was 73, 240, and 150 days, respectively. Patients with RCDI that failed multiple vancomycin tapers had symptom resolution following fidaxomicin therapy. All 3 regimens provided a greater SFI compared to a vancomycin taper. No patient experienced RCDI following FID-TP. FID-CH had the longest SFI, yet follow-up time with FID-TP was shorter given more recent adoption of this regimen. These results suggest the utility of using fidaxomicin to treat RCDI. (M. M. Soriano et al. Abstract 42591; presentation No. 1410; IDWeek, 5 Oct. 2013).
The use of fidaxomicin for the treatment of Clostridium difficile infections (CDI) or Clostridium difficile associated diarrhea or disease (CDAD) in an adult patient wherein the dosage regime is selected from the group consisting of:                a. 200 mg of fidaxomicin BID (Latin: bis in die; which means twice a day) for 20 days (reference example Model A)        b. 200 mg of fidaxomicin BID for 5 days followed by 5 days of rest and then 200 mg BID for a further 5 days (double pulse) (reference example Model B)was mentioned by C. H. Chilton during the ICAAC congress in September 2013 (reference example; C. H. Chilton et al. (2013) in J. Antimicrobial Chemotherapy Advance Access September 2013 and C. H. Chilton et al., abstract 23rd European Congress of Clinical microbiology & Infectious Disease, Apr. 27-30, 2013, Berlin).        
However, there still is a need to find a modified dosing regimen for tiacumicin compounds and in particular for fidaxomicin that combines efficacy, recovery of gut micro flora or a reduced effect on gut microflora, a reduction of recurrence, and a low chemical burden to the patients with cost-effectiveness.